Cryptococcus neoformans infections pose a significant challenge to human health, particularly due to the lack of effective drugs and the severe side effects of those currently available. This study aimed to evaluate the efficacy of a purified compound, 3-ethyl-6,7-dihydroxy-2-phenyl-chromen-4-one (EDPC), extracted from Alpinia officinarum, in comparison to fluconazole, in treating rat models infected with C. neoformans. A total of 120 rats were divided into six groups: a negative control group, a group infected with 1 × 104 CFU/mL of C. neoformans (positive control), and four treatment groups receiving either 10 mg/kg, 20 mg/kg, or 30 mg/kg of EDPC, or 10 mg/kg of fluconazole. Colony-forming units (CFU) in the lungs were measured at 7, 14, 21, 28, 35, 42, and 49 days post-infection. The results showed that treatment with EDPC, at all doses, as well as fluconazole, significantly increased survival rates and reduced lung CFU counts in infected rats. Histological analysis revealed notable improvements in lung tissue across the treated groups. Additionally, levels of pro-inflammatory cytokines TNF-α, IL-1β, and IL-17 were markedly reduced in animals treated with EDPC compared to the untreated infected group. Antioxidant activity was observed, with increased glutathione (GSH) levels and decreased malondialdehyde (MDA) levels in treated rats. Moreover, EDPC treatments helped normalize biomarkers related to liver and kidney function, while fluconazole was associated with a significant increase in renal biomarkers, indicating potential kidney toxicity. In contrast, EDPC demonstrated a safer profile regarding kidney function, making it a promising therapeutic agent for C. neoformans infections for long-term use.